U.S. patent application number 10/484838 was filed with the patent office on 2004-12-16 for process for the preparation of 2-(2-(4-(bis(4-fluorophenyl)methyl)-piperaz- in-1-yl)ethoxy)acetic acid derivatives or corresponding salt forms thereof and intermediates therefor.
Invention is credited to Diouf, Ousmane, Surtees, John.
Application Number | 20040254375 10/484838 |
Document ID | / |
Family ID | 8178144 |
Filed Date | 2004-12-16 |
United States Patent
Application |
20040254375 |
Kind Code |
A1 |
Diouf, Ousmane ; et
al. |
December 16, 2004 |
Process for the preparation of
2-(2-(4-(bis(4-fluorophenyl)methyl)-piperaz- in-1-yl)ethoxy)acetic
acid derivatives or corresponding salt forms thereof and
intermediates therefor
Abstract
The present invention relates to a process for the manufacture
of 2-{2-[4-(bis(4-fluorophenyl)methyl)-1-piperazinyl]ethoxy}acetic
acids, amides or related derivatives, of the general formula (I)
wherein: Y represents hydroxy or --NR.sub.1R.sub.2; R.sub.1 and
R.sub.2 each independently represent hydrogen or C?1-4#191 alkyl; m
is 1 or 2, and n is 1 or 2, as well as the non-toxic,
pharmaceutically acceptable salts and mixtures thereof. The present
invention concerns also a polymorphic form of efletirizine. 1
Inventors: |
Diouf, Ousmane; (Flines Lez
Raches, FR) ; Surtees, John; (Jezus-Eik (Overijse),
BE) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
8178144 |
Appl. No.: |
10/484838 |
Filed: |
January 26, 2004 |
PCT Filed: |
July 22, 2002 |
PCT NO: |
PCT/EP02/08157 |
Current U.S.
Class: |
544/398 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 11/08 20180101; C07D 295/088 20130101; A61P 17/00 20180101;
A61P 11/02 20180101; A61P 25/08 20180101; A61K 31/495 20130101;
A61P 17/04 20180101; A61P 37/08 20180101 |
Class at
Publication: |
544/398 |
International
Class: |
C07D 241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 26, 2001 |
EP |
01118131.0 |
Claims
1-23. (cancelled).
24. A process for the manufacture of
2-(2-(4-(bis(4-fluorophenyl)methyl)-1-
-piperazinyl]ethoxylaceticacids, amides and related derivatives of
the general formula (I) 17wherein: Y represents hydroxy, or
--NR.sup.1R.sup.2; R.sup.1 and R.sup.2 each independently represent
hydrogen or C.sub.1-4 alkyl; m is 1 or 2, and n is 1 or 2, as well
as non-toxic, pharmaceutically acceptable salts, and mixtures
thereof which comprises a) reacting compound of formula (II)
18wherein L.sup.1 represents a leaving group with a compound of
formula (III) 19wherein n and m are defined as above, in the
presence of a base and an inert solvent, and b) reacting the
corresponding compound of formula (IV) thus obtained 20with a
compound of formula (V) 21wherein L.sup.2 represents a leaving
group and Y is defined as above, In the presence of an inert
solvent and a proton acceptor.
25. The process according to claim 24 wherein n is 2.
26. The process according to claim 24 wherein m is 1.
27. The process according to claim 24 wherein L.sup.1 and L.sup.2
represent, independently, halogen or a sulfonic ester group.
28. The process according to claim 24 wherein L.sup.1 represents
chlorine.
29. The process according to claim 24 wherein L.sup.2 represents
bromine.
30. The process according to claim 24 wherein the base in step (a)
is selected from the group consisting of alkali metal carbonates,
hydroxides and organic tertiary amines.
31. The process according to claim 30 wherein said base is sodium
carbonate or potassium carbonate.
32. The process according to claim 24 wherein the proton acceptor
in step (b) is selected from the group consisting of alkali metal
hydrides, alkali metal hydroxides, alkali metal alkoxides and
alkali metals.
33. The process according to claim 32 wherein said proton acceptor
is sodium hydride or sodium methoxide.
34. The process according to claim 24 wherein the inert solvent is
selected from the group consisting of aliphatic and aromatic
hydrocarbons, ethers, amides and alcohols of low reactivity.
35. The process according to claim 34 wherein the inert solvent is
hexane, toluene, methyl ethyl ketone (MEK), dimethoxyethane (DME),
tetrahydrofuran (THF), dimethylformamide (DMF) or tert-butanol.
36. A process for the manufacture of a compound of formula (IV)
22wherein m is 1 or 2, and n is 1 or 2, as well as non-toxic,
pharmaceutically acceptable salts, and mixtures thereof, which
comprises reacting a compound of formula (II) 23wherein L.sup.1
represents a leaving group, with a compound of formula (III)
24wherein n and m are defined as above, in the presence of a base
and an inert solvent.
37. A process for the manufacture of
2-(2-[4-(bis(4-fluorophenyl)methyl)-1- -piperazinyl]ethoxy)acetic
acids, amides and related derivatives of the general formula (I)
25wherein Y represents hydroxy or --NR.sup.1R.sup.2; R.sup.1 and
R.sup.2 each independently represent hydrogen or C.sub.1-4 alkyl; m
is 1 or 2, and n is 1 or 2, as well as non-toxic, pharmaceutically
acceptable salts and mixtures thereof, which comprises reacting a
compound of formula (IV) 26wherein m and n are defined as above,
with a compound of formula (V) 27wherein L.sup.2 represents a
leaving group and Y is defined as above, in the presence of an
inert solvent and a proton acceptor.
38. A process according to claim 24 or 37, wherein the compound
obtained is a polymorphic form of the compound of formula (I)
wherein n is 2, m is 1 and Y represents OH.
39. A process comprising following steps a) precipitating of the
compound obtained by the process according to claim 24 or claim 37,
in its dihydrochloride form, b) washing the obtained precipitate
with a suitable organic solvent, c) re-dissolving the washed
precipitate in an aqueous medium, d) adjusting the pH of the
aqueous medium to about 7 with a suitable base or buffer, e)
extracting the re-dissolved product with a suitable organic
solvent, f) washing the obtained organic layer, g) drying said
obtained organic layer, followed by acidification with HCl, and h)
finally precipitating and drying the obtained dihydrochloride salt,
and wherein the compound obtained is a polymorphic form of the
compound of formula (I) wherein n is 2, m is 1 and Y represents
OH.
40. Process according to claim 39, wherein the suitable organic
solvent in steps b) and e) is methyl ethyl ketone.
41. A compound obtained by any of the processes according to claim
24 or 37.
42. A polymorphic form of efletirizine, obtainable by the processes
according to claim 24 or 37.
43. A polymorphic form according to claim 42 wherein its
crystallographic X-ray diffraction pattern presents peaks at
2.theta. values (.+-.0.5)) of: 7.000.degree.; 8.095.degree.;
12.000.degree.; 13.645.degree.; 14.085.degree.; 14.315.degree.;
14.870.degree.; 16.460.degree.; 17.295.degree.; 18.255.degree.;
18.755.degree.; 19.470.degree.; 20.575.degree.; 20.890.degree.;
21.660.degree.; 22.210.degree.; 22.890.degree.; 23.390.degree.;
24.210.degree.; 24.580.degree.; 25.130.degree.; 26.775.degree.;
27.855.degree.; 28.815.degree.; 29.820.degree.; 30.255.degree.;
31.460.degree.; 32.145.degree.; 32.890.degree.; 33.830.degree.;
34.695.degree.; 35.940.degree.; 38.135.degree.; 39.670.degree.;
43.065.degree.; 44.335.degree.; 46.210.degree.; 48.720.degree..
44. A polymorphic form of efletirizine characterized in that its
crystallographic X-ray diffraction pattern presents peaks at
2.theta. values (.+-.0.5)) of: 7.000.degree.; 8.095.degree.;
12.000.degree.; 13.645.degree.; 14.085.degree.; 14.315.degree.;
14.870.degree.; 16.460.degree.; 17.295.degree.; 18.255.degree.;
18.755.degree.; 19.470.degree.; 20.575.degree.; 20.890.degree.;
21.660.degree.; 22.210.degree.; 22.890.degree.; 23.390.degree.;
24.210.degree.; 24.580.degree.; 25.130.degree.; 26.775.degree.;
27.855.degree.; 28.815.degree.; 29.820.degree.; 30.255.degree.;
31.460.degree.; 32.145.degree.; 32.890.degree.; 33.830.degree.;
34.695.degree.; 35.940.degree.; 38.135.degree.; 39.670.degree.;
43.065.degree.; 44.335.degree.; 46.210.degree.; 48.720.degree..
45. A pharmaceutical composition comprising said polymorphic form
of efletrizine according to claim 42 in association with a
pharmaceutically acceptable adjuvant, diluent or carrier.
46. A compound of formula (IV) 28wherein m is 1 or 2, and n is 1 or
2, as well as non-toxic, pharmaceutically acceptable salts, and
mixtures thereof.
Description
[0001] The present invention relates in a first aspect to a new and
improved process for the preparation of
2-{2-[4-(bis(4-fluorophenyl)methy- l)-1-piperazinyl]ethoxy}acetic
acid derivatives or corresponding salt forms thereof. Said
compounds, and in particular 2-{2-[4-[bis(4-fluorophe-
nyl)methyl)-1-piperazinyl]ethoxy}acetic acid commonly known as
efletirizine, have been proven useful as therapeutic agents for the
treatment of allergic diseases and other disorders.
[0002] In a second aspect, the present invention relates to a new
polymorphic form of efletirizine. A process for the preparation of
this new polymorphic form and pharmaceutical compositions
containing it are also comprised within this invention.
[0003] Efletirizine has been found to possess excellent
antihistaminic properties. It belongs to the pharmacological class
of second generation histamine H.sub.1-receptor antagonists and
shows in vitro high affinity and selectivity for H.sub.1-receptors.
Efletirizine is useful as an antiallergic, antihistaminic,
bronchodilator and antispasmodic agent. Recent clinical studies
have shown the utility of efletirizine when administered in the
form of a nasal spray for the treatment of allergic rhinitis and
rhino-conjunctivitis (J.-F. Dessanges et al. Allergy and Clin.
Immunol. News (1994), Suppl. n.sup.o 2, abstract 1864; C. De Vos et
al., Allergy and Clin. Immunol. News (1994). Suppl. n.sup.o 2,
abstract 428). Another recent clinical pharmacological study has
shown that efletirizine gives unexpectedly good results in the
treatment of urticaria, atopic dermatitis and pruritis.
[0004] In the light of the versatility of efletirizine as a
powerful drug for the treatment of allergic and other diseases, a
new, low cost, easy to perform and high yielding process for its
preparation is desirable.
[0005]
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazinyl]ethoxy}acetic
acid or efletirizine, in the form of its dihydrochloride salt has
the following formula: 2
[0006] Efletirizine is encompassed within the general formula of
European Patent No. 0 058 146 and may be prepared according to the
general process described in this patent. Said process for the
synthesis of 2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}acetic
acid derivatives comprises reacting a 1-(diphenylmethyl) piperazine
derivative with methyl(2-chloroethoxy)acetate or 2-(2-chloroethoxy)
acetamide to form a methyl
2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}-acetate or a
2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}acetamide,
respectively. Thus the formed methyl ester or acetamide is then
subjected to basic hydrolysis followed by acidification and
isolation of the free carboxylic acid. This material is then
transformed Into its dihydrochloride salt.
[0007] European Patent N.sup.o 1 034 171 describes two
pseudo-polymorphic forms of efletirizine. There is a desire for an
alternative economical and high yielding process for the synthesis
of efletirizine.
[0008] According to the present invention, a new process for the
synthesis of
2-{2-[4-(bis(4-fluorophenyl)methyl)-1-piperazinyl]ethoxy}acetic
acids and their corresponding salt forms is provided. In
particular, said new process can be employed for the synthesis of
efletirizine and markedly overcomes several disadvantages of the
known methods.
[0009] In a first aspect, the present invention concerns a process
for the manufacture of
2-{2-[4-(bis(4-fluorophenyl)methyl)-1-piperazinyl]ethoxy}a- cetic
acids, amides and related derivatives of the general formula (I)
3
[0010] wherein: Y represents hydroxy or --NR.sup.1R.sup.2: R.sup.1
and R.sup.2 each independently represent hydrogen or C.sub.1-4
alkyl; m is 1 or 2, and n is 1 or 2,
[0011] as well as non-toxic, pharmaceutically acceptable salts and
mixtures thereof, characterized by
[0012] (a) reacting compound of formula (II) 4
[0013] wherein L.sup.1 represents a leaving group, with a compound
of formula (III) 5
[0014] wherein n and m are defined as above, in the presence of a
base and an inert solvent, and
[0015] (b) reacting the corresponding compound of formula (IV) thus
obtained 6
[0016] with a compound of formula (V) 7
[0017] wherein L.sup.2 represents a leaving group and Y is defined
as above, in the presence of an inert solvent and a proton
acceptor.
[0018] The term "leaving group", as used herein, has the same
meaning by the skilled man (Advanced Organic chemistry: reactions,
mechanisms and structure--Third Edition by Jerry March, John Wiley
& Sons Ed.; 1985 page 179) and represents a group which is part
of and attached to a substrate molecule. In a reaction where the
substrate molecule undergoes a displacement reaction (with for
example a nucleophile), the leaving group is then displaced.
Examples of leaving group are alkoxy, alkylthio, trimethylamino,
methylsulfinyl, methylsulfonyl or halogen. Preferably the leaving
group is halogen or a sulfonic ester group. The term "halogen", as
used herein, includes an atom of Cl, Br, F, I.
[0019] The term "sulfonic ester group", as used herein, has the
same meaning by the skilled man (Advanced Organic chemistry:
reactions, mechanisms and structure--Third Edition by Jerry March,
John Wiley & Sons Ed.; 1985 pages 311-312) and represents a
reactive ester. Since hydroxide does not leave readily from
ordinary alcohols, it must be converted to a group that does leave;
one way is conversion to a reactive ester, such as a sulfonic
group. The sulfonic acids groups tosylate (paratoluenesulfonates)
and mesylate (methanesulfonates) can be used. The term "sulfonic
acid", as used herein, represents a group of the formula
--SO.sub.3H.
[0020] According to a preferred embodiment, the present invention
is particularly suited for the manufacture of a compound of formula
(I) as described above, wherein n is 2. According to a preferred
embodiment, the present invention is particularly suited for the
manufacture of a compound of formula (I) as described above,
wherein m is 1.
[0021] Particularly preferred is
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-pip- erazinyl]ethoxy}acetic
acid (also known as efletirizine). These are especially preferred
as dihydrochlorides.
[0022] According to another preferred embodiment, in the compound
of formula of (II), L.sup.1 represents chlorine.
[0023] According to another preferred embodiment, in the compound
of formula of (V), L.sup.2 represents bromine.
[0024] Suitable bases for use in the step a) are alkali metal
carbonates, hydroxides and organic tertiary amines. Sodium and
potassium carbonate are preferred.
[0025] As proton acceptor for use in the step b) alkali metal
hydrides, alkali metal hydroxides, alkali metal alkoxides and
alkali metals are prefered. Sodium hydride and sodium methoxide are
especially preferred.
[0026] As solvent, any chemically inert solvent such as aliphatic
and aromatic hydrocarbons, ethers, amides and alcohols of low
reactivity may be used. Preferred solvents are hexane, toluene,
methyl ethyl ketone (MEK), dimethoxyethane (DME), tetrahydrofurane
(THF), dimethylformamide (DMF) or tert-butanol.
[0027] The process of this invention is particularly useful for the
production of
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazinyl]ethoxy}ac- etic
acid (efletirizine) in the form of its dihydrochloride.
[0028] In another embodiment, the invention concerns a process for
the manufacture of a compound of formula (IV) 8
[0029] wherein m is 1 or 2, and n is 1 or 2, as well as non-toxic,
pharmaceutically acceptable salts and mixtures thereof,
characterized by reacting a compound of formula (II) 9
[0030] wherein L.sup.1 represents a leaving group, with a compound
of formula (III) 10
[0031] wherein n and m are defined as above, in the presence of a
base and an inert solvent.
[0032] In another embodiment, the invention concerns also a process
for the manufacture of
2-{2-[4-(bis(4-fluorophenyl)methyl)-1-piperazinyl]etho- xy}acetic
acids, amides and related derivatives of the general formula (I)
11
[0033] wherein: Y represents hydroxy or --NR.sup.1R.sup.2; R.sup.1
and R.sup.2 each independently represent hydrogen or C.sub.1-4
alky; m is 1 or 2, and n is 1 or 2, as well as non-toxic,
pharmaceutically acceptable salts and mixtures thereof,
characterized by reacting a compound of formula (IV) 12
[0034] wherein m and n are defined as above.
[0035] with a compound of formula (V) 13
[0036] wherein L.sup.2 represents a leaving group and Y is defined
as above, in the presence of an inert solvent and a proton
acceptor.
[0037] The following description relates to the manufacturing
process of efletirizine. However, it will be apparent to those
skilled in the art that said compound can be interchanged with any
other compound encompassed by the general formula (I) as given
above.
[0038] In general, the new manufacturing process for efletirizine
consists of two major steps. The first step is the reaction of
bis(4-fluorophenyl)methylchloride with
N-(2-hydroxyethyl)piperazine. The substitution of the chlorine atom
of the bis(4-fluorophenyl)methyl moiety is performed in the
presence of a base because hydrogen chloride (HCl) is generated
during the reaction. This HCl would tend to interact with the free
amine functionality of the piperazine starting material, rendering
it inactive and therefore has to be neutralised in order to achieve
optimum conversion (and therefore yield).
[0039] Both mineral and organic bases can be used for said purpose,
such as alkali metal carbonates, hydroxides and organic tertiary
amines. For convenience of work up (product isolation) and lower
cost, it is generally fairly preferable to carry out the reaction
in the presence of alkali metal carbonates (such as potassium and
sodium carbonates). The most appropriate organic base is
triethylamine.
[0040] An alternative is to use the starting materials or the final
products themselves as base, since they contain basic nitrogen
(i.e. amine) functionality in the form of the piperazine moiety--as
noted above, these would react with excess HCl. In the case where
the starting material acts as base, at least two equivalents of it
are necessary to bring the reaction to completion. Although this is
in principle an alternative approach, it is preferred to avoid this
methodology since it leads to waste of more expensive starting
material and/or to necessity of recycling.
[0041] The second step in the manufacturing of efletirizine
consists of several stages. The second step is classically
identified as a "one-pot reaction" since all stages may be realised
successively and/or simultaneously in the same reactor.
[0042] First a proton acceptor is used to deprotonate the starting
material,
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazinly]ethanol. In
principle, any proton acceptor known to those skilled in the art
can be used, such as alkali metal hydrides, alkali metal
hydroxides, alkali metal alkoxides and alkali metals. For the
preparation of efletirizine, both sodium hydride (NaH) and sodium
methoxide (CH.sub.3ONa) are preferred.
[0043] Use of CH.sub.3ONa leads to the formation of methanol, which
is easily removed by distillation or evaporation under reduced
pressure. From the industrial safety viewpoint CH.sub.3ONa is
preferable to NaH. These deprotonation reactions are depicted in
scheme 1 below. 14
[0044] In a following step, the sodium alkoxide obtained is reacted
with a salt of a haloacetic acid, such as sodium bromoacetate or
its chloro analogue, and not directly with the corresponding
haloacetic acids. It is obvious that the alkoxide would simply be
inactivated in the presence of an acid by a classical acid-base
reaction resulting in its re-protonation to the corresponding
alcohol.
[0045] To circumvent this inactivation the halogenoacetic acid
derivative may be used in a corresponding salt form. This is why in
the case of bromoacetic acid, it is preferred first to treat the
acidic derivative with sodium hydride before reacting it with the
alkoxide obtained during step 1. In the case of chloroacetic acid,
the sodium chloroacetate derivative is already commercially
available. The condensation reaction between the alkoxide and
sodium bromoacetate is shown in detail in scheme 2 below. 15
[0046] The obtained efletirizine can easily be converted into its
dihydrochloride form. Therefore, the sodium salt of efletirizine
obtained as end product in the second step of the manufacturing
process is dissolved in water and the resulting solution then
acidified, preferably with aqueous hydrochloric acid solution
(preferably to a pH of about 1).
[0047] The new manufacturing process of this invention has several
advantages compared to the prior art method as described above in
the background of this invention.
[0048] For instance, the process of this invention no longer
utilises piperazine as such but instead a piperazine intermediate
is used. Said piperazine intermediate e.g.
N-(2-hydroxyethyl)piperazine or a similar compound of formula
(III), comprises only one single reactive nitrogen compared to
piperazine itself having two reactive sites. In the prior art
method said piperazine is used both as reaction product and as base
at the same time. The excess of piperazine has to be recovered at
the end of the reaction requiring an expensive recycling process.
On the contrary, in the process of this invention, inexpensive
mineral bases such as sodium carbonate can be used, with no
necessity for recycling.
[0049] Furthermore, condensation of
bis(4-fluorophenyl)methylchloride (DFBCl) with
N-(2-hydroxyethyl)piperazine requires very little excess of said
piperazine intermediate (0.5 equivalents in excess), whereas in the
prior art method quite a large excess of piperazine is needed (4
equivalents in excess).
[0050] As a result, the manufacturing process of this invention is
much cheaper and more economical compared to the prior art method
as described in EP Patent No. 58 146 and other methods currently
employed. In addition, in this invention 2-chloroethoxy acetamide
(CEA) is not used, again lowering the production cost
significantly. Other starting materials for use in the process of
this invention are also inexpensive.
[0051] The new process is less time consuming, uses less expensive
starting materials and does not require any recycling process to
recover unused reagents. Therefore, this process is economically
more favorable compared to the manufacturing process currently
employed. Furthermore, very high yields can be obtained by this
process, constituting a considerable technical advantage with
respect to other known methods in particular in the process
described in European Patent No. 0 058 146.
[0052] In another aspect, the present invention provides a process
for the preparation of a new polymorphic form of efletirizine. Said
polymorphic form is characterized by its particular X-ray
diffraction pattern as described in full below.
[0053] The invention also encompasses said new polymorphic form
itself, particularly as obtainable by the process according to the
invention, as well as pharmaceutical compositions comprising said
form in association with a pharmaceutically acceptable adjuvant,
diluent or carrier.
[0054] A preferred method for obtaining said new polymorphic form
of efletirizine comprises following steps
[0055] (a) precipitating of the compound obtained by the process
according to the invention in its dihydrochloride form,
[0056] (b) washing the obtained precipitate with a suitable organic
solvent,
[0057] (c) re-dissolving the washed precipitate in an aqueous
medium,
[0058] (d) adjusting the pH of the aqueous medium to about 7 with a
suitable base or buffer,
[0059] (e) extracting the re-dissolved product with a suitable
organic solvent,
[0060] (f) washing the obtained organic layer,
[0061] (g) drying said obtained organic layer, preferably over
magnesium sulphate, followed by acidification with HCl, and
[0062] (h) finally precipitating and drying the obtained
dihydrochloride salt.
[0063] The organic solvent used in steps b) and e) is preferably a
ketone or an ether. Most preferably methyl ethyl ketone (MEK) is
used
[0064] The base or buffer used in step d) is generally an inorganic
base, preferably an alkali metal carbonate or hydroxide. Most
preferably potassium carbonate is used.
[0065] The washed precipitate obtained after step b) is preferably
dried before being re-disolved in an aqueous medium according to
step c).
[0066] Said new polymorphic form of efletirizine can be
characterized by its crystallographic X-ray diffraction pattern and
presents peaks at 2.theta. values (.+-.0.5) of: 7.000.degree.;
8.095.degree.; 12.000.degree.; 13.645.degree.; 14.085.degree.;
14.315.degree.; 14.870.degree.; 16.460.degree.; 17.295.degree.;
18.255.degree.; 18.755.degree.; 19.470.degree.; 20.575.degree.;
20.890.degree.; 21.660.degree.; 22.210.degree.; 22.890.degree.;
23.390.degree.; 24.210.degree.; 24.580.degree.; 25.130.degree.;
26.775.degree.; 27.855.degree.; 28.815.degree.; 29.820.degree.;
30.255.degree.; 31.460.degree.; 32.145.degree.; 32.890.degree.;
33.830.degree.; 34.695.degree.; 35.940.degree.; 38.135.degree.;
39.670.degree.; 43.065.degree.; 44.335.degree.; 46.210; 48.720.
[0067] In another embodiment, the invention concerns also a
compound obtained by the process described above, such as
intermediates.
[0068] According to a preferred embodiment, such a compound is a
compound of formula (IV) 16
[0069] wherein m is 1 or 2, and n is 1 or 2, as well as non-toxic,
pharmaceutically acceptable salts and mixtures thereof.
[0070] The present invention will be better understood from the
following examples which only serve to illustrate the invention and
therefore should not be taken to limit the scope thereof.
EXAMPLES
Example 1
Preparation of
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazinyl]ethanol
[0071] In a 300 ml reactor equipped with a reflux condenser,
introduce 0.016 mole, 2.65 g of potassium iodide (15% compared to
bis(4-fluorophenyl)methylchloride (DFBCl)), 0.158 mole of sodium
carbonate (Na.sub.2CO.sub.3) (1.5 equivalents compared to DFBCl),
100 ml of methyl ethyl ketone (MEK) (4 volumes compared to DFBCl
and 0.158 mole, 20.6 g of N-(2-hydroxyethyl)piperazine (1.5
equivalents). Heat up the reaction mixture to 90.degree. C. Once
reflux has started, add dropwise 0.105 mole, 25 g of DFBCl over a
30 minutes period and let the mixture stir for 2 hours. Evaporate
the MEK, resuspend the residue in 400 ml of water and extract twice
with 100 ml of diisopropylether (DIPE). Add 100 ml of water to the
organic phase and adjust the pH of the aqueous phase to 2.4 with
aqueous HCl 37%. Wash the aqueous phase 3 times with 100 ml of
toluene, then basify the aqueous phase with sodium hydroxide 50%.
Extract the aqueous phase 3 times with 100 ml of toluene. Wash the
toluene phase with 100 ml of demineralized water and eliminate
residual water by azeotropic distillation. Evaporate the
toluene.
[0072] Following this process, 29 g of
2-{2-[4-[bis(4-fluorophenyl)methyl)- -1-piperazinyl]ethanol was
obtained, i.e. a yield of 83% (HPLC analysis 99.9%).
Example 2
2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic
acid
Example 2A
Reaction in the Presence of NaH as Proton Acceptor
[0073] 5 g of the obtained
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazin- yl]ethanol in
example 1 is introduced into a reactor in the presence of anhydrous
THF (50 ml) and NaH (2.5 equivalents). This is heated at 50.degree.
C. and bromoacetic acid (1.3 equivalents) is added. The reaction is
allowed to proceed overnight. Evaporate the THF, resuspend the
residue in 100 ml of water (formation of 3 phases). Recover the
intermediate phase, and take it up in 100 ml of water. Acidify with
a solution of HCl 37% until homogenization of the medium (pH 1).
Wash the aqueous phase with three times 100 ml toluene, concentrate
the water until appearance of a white precipitate. Let it
precipitate completely overnight at 4.degree. C. in the
refrigerator. Filter the precipitate, wash it with MEK and dry
it.
[0074] Following this process.
2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piper- azinyl]ethoxy]acetic
acid dihydrochloride was obtained with a yield of 96% and purity of
97.4%.
Example 2B
Reaction in the Presence of CH.sub.3ONa as Proton Acceptor
[0075] In a 300 ml reactor, introduce 0.09 mole, 30 g of
2-{2-[4-[bis(4-fluorophenyl)methyl)-1-piperazinyl]ethanol such as
described in example 1, 120 ml of toluene and carefully add 12.15
of sodium methoxide (2.5 equivalents) slowly. Allow to stir for 10
hours at room temperature then evaporate the solvent. Take up the
residue in 160 ml of tetrahydrofuran (THF) and add 16.4 g of sodium
bromoacetate (1.3 equivalents). Heat up the mixture to 50.degree.
C. and let it stir overnight. Evaporate the THF, resuspend the
residue in 100 ml of water (formation of 3 phases). Recover the
intermediate phase, and take it up in 100 ml of water. Acidify with
a solution of HCl 37% until homogenization of the medium (pH 1).
Wash the aqueous phase with three times 100 ml toluene, concentrate
the water until appearance of a white precipitate. Let it
precipitate completely overnight at 4.degree. C. in the
refrigerator. Filter the precipitate, wash it with MEK and dry
it.
[0076] Following this process, 37 g of
2-{2-[4-[bis(4-fluorophenyl)methyl)- -1-piperazinyl]ethoxy}acetic
dihydrochloride was obtained, i.e. a yield of 87.7% (HPLC analysis
97.4%).
Example 3
Preparation of a New Polymorphic Form of
2-[2-[4-[bis(4-fluorophenyl)methy- l]-1-piperazinyl]ethoxy]acetic
acid dihydrochloride (efletirizine)
[0077] The dried powder obtained from Example 2B was re-dissolved
in water, the pH of the solution was brought to 7 using an aqueous
solution of potassium carbonate and extracted with methyl ethyl
ketone. The organic layer was washed with water, dried over
magnesium sulphate, filtered and gaseous HCl was introduced into
the solution. The dihydrochloride salt, which precipitated on
standing at +4.degree. C., was filtered, dried and analysed.
Analytical data for this material are as followed:
[0078] HPLC (Conditions: Column Bondapack C18 waters, 10 .mu.m,
3.9.times.300 mm) showed a purity of 100% area as assessed by peak
area.
[0079] Elemental Analysis:
1 % C % H % N Calculated: 54.44 5.66 6.05 Found: 53.52 5.69
6.11
[0080] Mass spectrum: MH.sup.+=391 (dihydrochloride salt)
[0081] Melting point: 222-224.degree. C.
[0082] DSC: Differential Scanning Calorimetry
2 20.degree. C./min: onset = 227.5.degree. C. 5.degree. C./min:
onset = 215.7.degree. C.
[0083] Infra-Red: 2950 cm.sup.-1 (nNH.sup.+); 1748 cm.sup.-1
(.nu.CO)
[0084] XRay powder diffraction: characteristic diffraction peaks
are observed at 2.theta. values (.+-.0.5): 7.000.degree.;
8.095.degree.; 12.000.degree.; 13.645.degree.; 14.085.degree.;
14.315.degree.; 14.870.degree.; 16.460.degree.; 17.295.degree.;
18.255.degree.; 18.755.degree.; 19.470.degree.; 20.575.degree.;
20.890.degree.; 21.660.degree.; 22.210.degree.; 22.890.degree.;
23.390.degree.; 24.210.degree.; 24.580.degree.; 25.130.degree.;
26.775.degree.; 27.855.degree.; 28.815.degree.; 29.820.degree.;
30.255.degree.; 31.460.degree.; 32.145.degree.; 32.890.degree.;
33.830.degree.; 34.695.degree.; 35.940.degree.; 38.135.degree.;
39.670.degree.; 43.065.degree.; 44.335.degree.; 46.210; 48.720.
* * * * *